The present invention, in some embodiments thereof, relates to bioadhesive matrices, and more particularly, but not exclusively, to bioadhesive matrices, to formulations and kits for forming same and to uses thereof for adhering two or more objects, including biological objects such as viable tissues, organs and the likes.
In recent years there has developed an increased interest in replacing or augmenting sutures and staples with bioadhesive matrices (also referred to in the art as bioadhesive compositions). The reasons for this increased interest include the potential speed with which internal surgical procedures might be accomplished; the ability of a bonding substance to effect complete closure, thus preventing seepage of fluids; the possibility of forming a bond without excessive deformation of the treated tissue; obviate the need for suture removal; cause less pain to the patient; its use requires simpler equipment which presents no risk of injury to the practitioner from sharp instruments; it provides lesser scar; and lowers the probability for infections.
Bioadhesives may also be used for sealing air and body fluid leaks, which may occasionally be resistant to conventional suture or stapling techniques; be used for topical wound closure; repair aortic dissections; and for internal and/or external fixation of certain devices.
Like any adhesive matrix, bioadhesive matrices are formed upon curing a corresponding formulation. Thus, the formulation is applied onto e.g., a biological object, and when subjected to mixing, curing initiators or other curing initiating conditions, cures so as to afford the bioadhesive matrix.
In order for bioadhesive matrices to be acceptable, they must possess a number of properties, such as biocompatibility and biodegradability, and optimal bonding strength and elasticity once cured. Further, the bioadhesive matrices should be designed such that the corresponding formulation exhibits a user-friendly consistency and curing/bonding time. More specifically, bioadhesive formulations should exhibit optimal initial viscosity and tack to allow adequate and easy application; not too fluid so as not to flow away from the wound edges and not too viscous so as to interfere with even and proper application, and at the same time solidify quickly with short curing/gelation time, yet, not too short curing/gelation time, so as to allow smooth application to the desired site. In addition, bioadhesive formulations/matrices should exhibit an ability to bond rapidly to living tissue under wet conditions of bodily fluids; the bioadhesive matrix should form a bridge, typically a permeable flexible bridge; and the bioadhesive formulation, matrix and/or its metabolic (biodegradation) products should not cause local histotoxic or carcinogenic effects, while not interfering with the body's natural healing mechanisms.
Bioadhesives can be used in many surgical procedures including corneal perforations, episiotomy, caesarian cases, cleft lip, skin and bone grafting, tendon repair, hernia, thyroid surgery, periodontal surgery, gingivectomy, dental implants, oral ulcerations, gastric varices wounds of internal organs such as liver and pancreas, attachment and immobilization of external and internal medical devices and more.
Fixing fractured hard tissues using an appropriate bioadhesive material instead of the traditional nailing and plating methods is also considered an attractive technique.
The advantages include providing an optimal load transfer from one fracture side to the other, avoiding stress-shielding phenomena and the ability to repair small or thin bone fragments. Yet, in spite of the clear medical necessity, there is no hard tissue bioadhesive product available for clinical use to date.
Several materials useful as tissue adhesives or tissue sealants are currently available.
One type of adhesive that is currently available is a cyanoacrylate adhesive.
Cyanoacrylates, such as 2-octyl cyanoacrylate, known as Dermabond®, create a strong bond to tissue, enables rapid hemostasis and have the ability to polymerize in contact with fluids that are present at the biological surfaces. However, cyanoacrylate adhesives were found to be cytotoxic, the viscosity of the pre-cured adhesive formulation is too low and the cured cyanoacrylate matrix is stiff and non-biodegradable, interfering with normal wound healing. Hence, non-optimal viscosity, high flexural modulus and reports of cancer in animal experiments limited the use of cyanoacrylates to surface application on oral mucosa and life threatening arteriovenous.
Other known bioadhesive formulations are based on gelatin-resorcinol-formaldehyde, wherein a mixture of gelatin and resorcinol is warmed and crosslinked within tens of seconds by the addition of formaldehyde. The advantage of bioadhesives formed from such formulations is adequate bonding strength; however, cytotoxicity overshadows the advantages.
Another type of a currently available bioadhesive which is used as a tissue sealant utilizes components derived from bovine and/or human sources. For example, fibrin-based adhesive formulations are typically prepared by mixing a solution of fibrinogen and factor XIII with a solution of thrombin and CaCl2. The two solutions are applied by a twin syringe equipped with a mixing nozzle, and the reaction is similar to white fibrin clot in blood clotting. Commercially available examples include Baxter Tisseel® and Ethicon Crosseal™. Advantages of fibrin-based bioadhesive matrices include hemostatic effect, biodegradability, good adherence to connective tissue and promotion of wound healing. Disadvantages include low strength (adhesive and cohesive), low viscosity (hard to apply only to the desired site) and risk of infection as in use of any human-origin product. In the United States fibrin adhesives are prepared from the patient's own blood in order to prevent contamination; however, this process is time consuming and expensive. Other limitations include air leakage in lung surgery that can reoccur a few days after surgery, possibly due to too-rapid absorption of the fibrin adhesive bridge.
Other known bioadhesives are protein-based tissue adhesives which are based on albumin or gelatin. The addition of polyamine, especially poly(lysine) or chitosan, or a polycarboxylate, especially citric acid or poly(acrylic acid), to increase the rate of crosslinking was also described. However, such bioadhesives are typically characterized by insufficient biocompatibility and strength.
Sung et al. [Journal of Biomedical Materials Research, Volume 46, Issue 4, pages 520-530, 15 Sep. 1999] report evaluation of various bioadhesive formulations including a formulation based on gelatin, alginate and carbodiimide.
However, the formulations reported by Sung et al., are based on about 600 mg/ml gelatin content or higher, which do not afford a workable bioadhesive formulation.
Additional background art include U.S. Patent Application Publication Nos. 20030083286, 20040156794, 20060013873, 20090098176, US20090099149 and 20110280952, and U.S. Pat. Nos. 5,284,659 and 5,955,502, and Hsu, S. et al., Biorheology, 2007. 44(1): p. 17-28; Otani, Y. et al., Biomaterials, 1996. 17(14): p. 1387-1391; Bae, S. K. et al., Journal of Adhesion Science and Technology, 2002. 16(4): p. 361-372; Mo, X. et al., Journal of Biomaterials Science, Polymer Edition, 2000. 11(4): p. 341-351; McDermott, M. K., et al., Biomacromolecules, 2004. 5(4): p. 1270; Mo, X. et al., Journal of Biomedical Materials Research Part A, 2010. 94(1): p. 326-332; and Okino, H., et al., Journal of Biomedical Materials Research Part A, 2002. 59(2): p. 233-245.